Breast Cancer

Mammography.  US NIH

Author : Dr Daniel Hayes Clinical Director of the Breast Oncology Program University of Michigan. Ann Arbor  2008-07-28

Breast Cancer : Breast Cancer is the most common lethal malignancy among women in the Western World. Approximately a quarter million American women will be diagnosed with breast cancer in 2007, and roughly 40,000 will die of it. However, remarkable scientific progress over the last four decades has led to important advances in clinical evaluation and management in several areas of breast cancer, including risk, prevention, screening, and treatment. These advances have resulted in substantially lower mortality while decreasing the adverse consequences of treatment.

Clinical Science

To fully understand much of the discussion about progress in breast cancer, it is worthwhile to take a brief digression into the importance of clinical science and how doctors make decisions. Classically, doctors have decided on a course of action for a patient based on their clinical experience or recommendations of others they perceive to be experts in the field. Over the last 10-15 years, many leaders in medicine have called for what is now termed “evidence-based” medicine, using results from scientific clinical studies to direct clinical decisions. Of course, the classic approach was based on evidence. For example, if a doctor gave penicillin to a patient with pneumonia and the patient improved, that doctor had evidence that penicillin is effective against pneumonia. However, this type of evidence is not very accurate and is not really based on the scientific method. In the scientific method, a scientist develops a hypothesis and then prospectively designs an experiment in which all conditions are controlled except a single variable, with appropriate negative controls to be certain that the observation of an effect (like the patient improving on penicillin) would not have happened anyway, or was simply due to chance alone. While we usually think of this method being used by laboratory scientists, it also pertains to clinical science.

Available evidence to guide clinical decisions has been placed into “levels” (which are really grades or scores), each of which is likely to provide a more accurate estimate of the truth of the observation than the next. For example, retrospective studies of populations (looking back) to see who did or did not get some type of disease can be compelling, but can be confounded by many variables that were not and cannot be controlled. It is clear that women in developed countries have a higher risk of breast cancer than those in agrarian and third world cultures. When one hears this, you might think of many different reasons why this is true, including dietary changes, exposure to environmental toxins, or higher rates of taking estrogen therapy. However, you might also conclude that driving expensive cars or watching color television might also be causative. This sort of clinical research is called epidemiology, and although it is valuable for developing new hypothesis, it is considered a lower level of evidence than the gold standard for clinical research: the prospective randomized clinical trial. In the latter, a group of subjects that are at risk for a particular occurrence, like developing breast cancer, are enrolled into a trial and assigned to a particular intervention (receipt of a drug or treatment) or not (often the usual standard of care medication or treatment, and sometime a placebo drug or no intervention) in a random fashion. For example, high-risk patients might be assigned to receive a drug for which preliminary, lower evidence studies have suggested a preventive role. Randomization is often done by computer, but not always.

Prospective randomized clinical trials are designed so that everyone in the study receives standard of care, but some are randomly assigned to an investigational arm that challenges the standard of care while the others are not. These trials are carefully reviewed by ethical review boards comprised of both scientists not involved in the trial as well as regular citizens from all walks of life. Once they are begun, the trials are carefully monitored to be certain that their ongoing conduct remains scientifically reasonable and ethically appropriate. Any patient who is considering being in such a trial should carefully discuss the risks and benefits of participating with his/her caregiver, and all patients who enter a clinical research study must sign a written consent form.

When completed, prospective randomized clinical trials usually provide a definitive answer regarding whether the investigational intervention is or is not preferable to standard of care. Indeed, not infrequently, several prospective randomized clinical trials addressing a similar issue are conducted by different scientists with similar ideas at the same time. If the design of these studies is sufficiently similar, the result of these studies can be combined into what is called a “meta-analysis” that, essentially, results in a “mega” study. Many clinical scientists consider these meta-analyses, or “overviews,” of many prospective randomized clinical trials to represent the highest level of evidence.

During the following discussions, I will refer to various studies and provide assessments as to the level of evidence that is available to guide doctors and patients while they make difficult clinical decisions. Fortunately, breast cancer investigators have a long and rich history of conducting prospective randomized clinical trials, dating to the 1940s, so that patients can be informed with reasonable confidence of the relative pros and cons of electing one type of clinical approach vs. another. However, of course, we still do not know all the answers, and ongoing prospective randomized clinical trials will continue to provide important answers for women at risk for, or who develop breast cancer in the future. Many studies have demonstrated that women who participate in such trials, even if they are randomly assigned to the “standard” arm, often have better outcomes than women treated in a standard fashion outside of the protocol, demonstrating that good clinical research is good clinical medicine.

Should you be in a clinical trial? This is a very personal decision. People participate in clinical trials for a number of reasons. Just by being in a trial, it is likely you will receive excellent care overall, and if you are receiving the investigational strategy, it is possible you will benefit. However, it is also possible that the investigational strategy will turn out not to be better than standard therapy, and it might even be associated with increased side effects. Most patients participate with the knowledge that regardless of the outcome of the trial, others will be helped. If the trial shows the investigational approach is better, then the next generation of patients will receive better overall treatment. If it is not, the trial will prevent the next generation from being exposed to the toxicities and cost of ineffective therapy. You should ask your doctor if there is a clinical trial available that is appropriate to your circumstances. If there is, you should read the consent form, which has been carefully written to describe the reasons behind the study and all of the potential risks and benefits of your participation, and discuss it in detail with your caregiver and your family and friends.

What is Breast Cancer?

The usual breast cancer begins in the cells that line the milk glands of the breast. These are called epithelial cells. The cancer may arise from the glands that actually initiate the milk production, called the “lobules,” or more commonly it may arise from the cells that line the ducts that normally transport the milk from the lobules to the nipple. In fact, 90% of breast cancers are felt to be ductal, while approximately 5% are lobular, and the rest are considered to have begun in the duct but have unusual appearances under the microscope and are called “special types.” These special types include “tubular,” “mucinous,” “colloid” and “medullary” breast cancers.

In general, ductal and lobular cancers have about the same prognosis, although lobular cancer has some odd characteristics that can make it harder to see on a mammogram and harder to detect when it spreads to lymph nodes. In addition, when lobular cancers spread (this process is called metastases), it often goes to unusual places in the body, like the lining of many body cavities. The special types are usually associated with very favorable prognosis.

Medullary cancers are particularly vexing. They have features under the microscope that make them appear to be very aggressive. However, if a patient has “classic” medullary cancer, her prognosis is quite good without any therapy except treatment of the cancer where it started with surgery and radiation. In contrast, if the medullary cancer is considered “atypical,” her prognosis is actually much poorer and chemotherapy is very likely to improve her long-term chance of survival.

Non-epithelial malignancies can arise in the breast, but they are very unusual. These can include sarcomas (cancers of fibrous, fat, or muscle cells) and lymphomas (cancers that arise from lymph cells). These cancers are treated as if they had arisen anywhere in the body, and those discussions are outside the scope of this review.

What Causes Breast Cancer?

No one knows for sure what exactly causes a normal cell to become breast cancer, or for that matter, any cancer. We do know that normal cells have built-in controls that permit them to divide sufficiently to maintain normal healthy tissue, but not more than is necessary. Normal cells are also unable to leave where they are supposed to do their normal job (such as in the breast duct) and travel to other sites. Cancer cells lose these internal controls; they divide too much and they are able to travel to other sites and grow (metastases). Over the last two decades, we have seen remarkable breakthroughs in understanding these processes. For example, all of our cells have genes that maintain these normal controls on cell growth, invasion, and spread. Indeed, if a cell has been irrevocably damaged during its normal division, there are even genetic programs that cause that cell to kill itself (this process is called “apoptosis”). These genes are called “tumor suppressor genes,” and we know that one cause of cancer is damage or deletion of one or more of these genes, so the rest of the genes in the cell go haywire. We also know that certain genes that are necessary for normal cell division, growth, and movement can develop mutations that result in uncontrolled activation, so that a cell loses its normal control. When these occur, these genes are called “oncogenes.”

For most patients, development of cancer appears to be a combination of a genetic propensity to develop cancer (for example, by inheriting abnormal tumor suppressor genes that do not do their job as well as normal ones do in other people), and exposure to environmental factors that induce or enhance the changes that result in cancer. Unlike lung cancer, for which smoking is a compelling causative factor, there have been no clearly identifiable causes for breast cancer. However, decades of epidemiologic research have demonstrated that breast cancer is clearly associated with female reproductive hormones, like estrogen and progesterone, either when taken as medicine or when made by the patient herself. For example, although men do get breast cancer, their risk is nearly 100-fold less than that for women. The risk for breast cancer is about two-fold higher for women who start their periods young (less than 13 years old) and who delay their first full term pregnancy into their 30s, while women who have a premature menopause appear to have a lower risk than those whose menopause extends into their 50s. We also know that estrogen therapy, especially when combined with progesterone, increases a woman’s risk of getting breast cancer. Ongoing research is addressing other possible causes, but so far none has been discovered.

No one knows for sure why estrogen causes breast cancer. However, over 100 years of clinical and laboratory research has demonstrated that about 65-75% of breast cancers require estrogen to live, spread, and grow. These types of breast cancer contain a molecule inside their cells called the “estrogen receptor.” Estrogen itself, either made by a woman or taken as medicine, floats through the bloodstream and diffuses (enters) into cells. Those cells that have the estrogen receptor inside of them capture the estrogen and then transmit a “go” signal to the nucleus. This system is a bit like an automobile that needs gasoline. You can think of the cell as the automobile, estrogen as gasoline, the estrogen receptor as a gas tank, and the nucleus of the cell as the engine. Estrogen receptor (called ER, for short), and its cousin, progesterone receptor (called PR) can be easily measured in breast cancer tissue, and it is standard practice to do so.

What makes breast cancers that do not need estrogen grow? Other factors have been found, the most important of which is a molecule called HER-2 (for Human Epithelial Receptor-2). About 20% of breast cancers make too much HER-2, which sits on the surface of the cell and controls and transmits signals from outside the cell down to the nucleus. Let’s continue with our automobile analogy. You might think of HER-2 as a solar panel. A car might get some or all of its energy from the sun, but it would need a solar panel to do so (don’t get confused, though: breast cancer has nothing to do with sun exposure, this is just an illustration). Most breast cancers that are positive for estrogen receptor do not make HER2, but some do. More estrogen receptor negative breast cancers make HER2. Regardless, breast cancers that make HER-2 are more aggressive than those that do not. There are many breast cancers (maybe 25%) that do not make ER, PR, or HER2; lately, these have been designated as “triple negative” cancers, in part because there is no specific therapy for them as there is for ER and HER-2.

Who gets Breast Cancer (Risk)?

The most important risk factors for developing breast cancer are being a woman and being older (over 50). More than 75% of breast cancers occur in this group of people. While breast cancer does occur in men, it is quite rare (about 100 fold less common than in women). Likewise, although 25% of all breast cancers do occur in women less than 50 years, most of these occur in women 40-50 years old. Breast cancer in women less than 40 is certainly seen, and the diagnosis must be considered in a young woman with a breast abnormality, but it is really not very common. In fact, other than being a woman over 50, known risk factors like family history and benign breast conditions can only be found in about 25% of all patients with breast cancer. This is called “attributable” risk (meaning that, of all the patients who have the disease, what percentage actually have the risk factor?). A great example of a very strongly-associated attributable risk factor is smoking for lung cancer. More than 90% of all patients with lung cancer have been or are smokers. A second kind of risk is called “relative risk.” In other words, if you have the risk factor, how much more likely are you to get the disease than someone without it. We have already discussed being female vs. male for breast cancer, for which there is a very high relative risk (more than 100-fold). Returning to lung cancer, subjects who have smoked for ten years or more have a 10-fold or higher relative risk of developing the disease than those who have not smoked. Most of the known risk factors for breast cancer, especially those with reasonably high attributable risks, such as reproductive history, only have relative risks of 2-fold or less. The final kind of risk is called “absolute” risk -- in other words, if you have the risk factor, how likely are you to actually get breast cancer over some period of time, such as the next five, 10, or 15 years? With a few exceptions, none of the known risk factors, even when combined into an index that takes several risks together, results in a very high absolute risk over a relatively short period of time. For example, Dr. Mitchell Gail and colleagues have created such an index to determine risk for individual women. Even those with several factors often only have an absolute risk of 3-5% over the succeeding five years.

Why determine these kinds of risks? First, they may provide insight for future research. For example, the observation that women are much more likely to get breast cancer than men led to the thought that the disease must be associated with female reproductive hormones, like estrogen and progesterone, and this observation has further led to remarkable clinical advances that have resulted in prevention and treatment of the disease. Second, if strategies to prevent and/or screen for the disease are known to be effective, they will be much more efficiently applied to those most likely to get it. In this case, attributable risks are the most important, to decide which populations should be included. For example, we don’t recommend screening mammograms for men, since such a small percentage of breast cancers occurs in men. Furthermore, even if his relative risk is elevated, for example by having a mother with breast cancer, a man’s absolute risk of developing breast cancer is still so low that it would essentially be a waste of time and resources. Finally, a patient’s absolute risk is the most powerful determinant of whether she should or should not participate in screening or treatment strategies personally, since one does not want to expose one’s self to the costs and toxicities of a given strategy if there is a very small, or no, chance of getting the disease. Incidentally, a version of the program developed by Dr. Gail and colleagues to calculate an individual’s risk of getting breast cancer over a five year period of time is available online at http://www.cancer.gov/bcrisktool/about-tool.asp and you can estimate your own chances of getting breast cancer if you’d like.

The risk of breast cancer is increased if a woman takes estrogen therapy, especially if it is associated with progesterone. A recently conducted prospective study in which postmenopausal women were randomly assigned to either take estrogen and progesterone therapy or neither was terminated early due, in part, to an excess of breast cancers in the treated group, an observation that is consistent with prior epidemiologic studies. When the results of this study were announced in 2003, the use of combined estrogen and progesterone therapy, which was widespread up to then, dropped precipitously in our society. In the last couple of years, the overall incidence of breast cancer has dropped in the U.S., presumably due to women discontinuing estrogen and progesterone use.

It is not clear if estrogen therapy alone increases the risk of breast cancer. Indeed, in a companion prospective trial to the one discussed above, women who had had a hysterectomy were randomly assigned to estrogen therapy alone or not. In the first study, progesterone had been added because it has been known for years that estrogen increases the risk of uterine cancer (cancer of the lining of the womb, which is also called the endometrium). Obviously, because the women in the second study had had their wombs removed, the risk protection from uterine cancer that the progesterone conferred was not felt to be needed. In this second trial, an increase in breast cancer has not been seen, suggesting that perhaps the increased risk in the first study was due to the progesterone, either itself, or perhaps because it couples adversely with estrogen.

It is not clear whether oral contraceptives (birth control pills) do or do not increase the risk of breast cancer. No trial has ever been conducted in which women are randomly assigned to get birth control pills or not, and the epidemiologic studies of this issue have been mixed. They are complicated to do because oral contraceptives come in many forms, with different doses of estrogen, with or without other hormones like progesterone, and women have taken them for different periods of time and in different phases of their lives. Overall, it seems reasonable to suggest that the benefits of birth control pills, with regard to preventing unwanted pregnancies, outweigh whatever small risk they might cause for breast cancer.

We don’t know why or how estrogen and progesterone cause a normal breast epithelial cell to become a cancer cell. Laboratory studies clearly show that these hormones are necessary and increase the growth of most, but not all, normal and cancerous breast cells. Indeed, doctors routinely measure the estrogen receptor in breast cancer tissue. The estrogen receptor (designated ER) permits the breast cell to pull estrogen out of the blood and use it to function. Anti-estrogenic therapy, which is the mainstay of treatment of breast cancer, only works in those women whose cancers make ER, as discussed in greater detail below. However, in laboratory studies, neither estrogen nor progesterone alone will make a normal breast cell become malignant, and many women have taken estrogen for years and do not develop breast cancer. Therefore, scientists believe that there must be an interaction between an inherent susceptibility to cancer for individual women and other, non-hormonal factors.

No one has identified any other definitive causes of breast cancer. Several different environmental and dietary factors have been suggested and heavily studied, but none has been shown to be a causative culprit. It is true that obese women, and women who drink moderate to large amounts of alcohol have a higher risk of breast cancer, but it is not known if these are causative or just related to something else that causes the cancer. Therefore there are no clear life-style changes that a woman can make to substantially reduce her risk of breast cancer (as there is for lung cancer: DO NOT smoke, or if you do, STOP). It is conceivable that delaying menarche (when a girl begins to menstruate) to an older age or electing to have a first full-term pregnancy at a young age (less than 21 years) will decrease risk. However, these are not terribly practical strategies and will only modestly reduce the risk for breast cancer.

Inherited, Genetic Risk1. Obviously, only a few women with exactly the same apparent risk factors will actually get breast cancer. The variability of who does or does not get breast cancer suggests that there may be factors that women inherit that make them more susceptible. For example, we know that other than being a woman over 50 years old, the most common risk factors are either having a family history or having had breast cancer yourself, suggesting these women are more susceptible and may have inherited the same risk factor that their family members inherited. In fact, scientists have worked very hard to identify abnormalities in genes that a woman has inherited from her mother or father that places her at high risk. About 15 years ago, two such genes were identified. They are called BRCA 1 and 2. When these function normally, BRCA1 and 2 are tumor suppressor genes. Everyone has two copies of these genes in their cells; one copy comes from your mother and the other from your father. For most women BRCA1 and 2 appear to function by preventing normal cells that make mistakes during division from becoming malignant. Normally, in all cell division, mistakes are occasionally made in many genes within the cell. BRCA1 and 2 appear to function by fixing these mistakes after the cell divides so they are not passed on in the next division, much like a spellchecker program finds and fixes mistakes in a wordprocessing manuscript. Mistakes also occur in BRCA1 and 2 in normal division. It appears very unlikely that mistakes occur in both copies of BRCA1 or 2 at the same time. Thus, the remaining normal copy can go about its business fixing other genes while the “broken” copy of BRCA1 or 2 is fixed, itself. In this case, the other genes all get fixed, and before the cell divides, it has been returned to having two normal copies of BRCA1 or 2. This situation is analogous to being born with two good legs; if one is fractured, you can walk with a crutch until it is healed, and then you are fine.

In a few families, one or the other copies of the BRCA 1 or2 gene is abnormal to begin with in every cell. Therefore, only one copy is working. This is fine for most of the time, but if the only normal copy of BRCA1 or 2 is damaged, there is no “backup” second copy (since it never worked). In this case, cells that in the ordinary course may sustain damage to other genes are in danger of having no repair backup, and becoming malignant. Using our “leg” analogy, if you are born with only one good leg, you can walk with help, but if that leg is damaged, you fall down.

BRCA1 and 2, if abnormal, confer enormous relative risk for the populations that have them (10-fold or higher), and absolute risk for those affected individuals. Up to 60% or more of women who are born with abnormal BRCA1 or 2 genes will develop breast cancer by the time they are 60 years old, and they are much more likely to get the cancer at an early age and more than once. Furthermore, they are also at risk for some other cancers, especially ovarian cancer. Incidentally, these women are often said to be “positive” for these genes, but of course what we really mean is that they are “positive” for having abnormal copies of the genes. However, BRCA 1 and 2 are very low attributable risk genes. Only about 5% of women with breast cancer are found to have abnormal inherited copies of these genes, and the rest are born with normal copies.

Should you be tested to see if you have abnormal BRCA 1 or 2 genes? For most women, the answer is no. The odds of the average woman being abnormal are quite low, and although the test only requires a simple blood draw, it is technically difficult and expensive to perform. Furthermore, on occasion it provides false positive testing, or more commonly the results are equivocal (meaning that it finds unusual changes, but the clinical significance of these is unknowns). Therefore, panels of experts have recommend that testing only be performed for those women most likely to be positive. These include one or more of the following:
Personal age <40 years at time of breast cancer diagnosis
Ashkenazi Jewish Heritage
Personal or first or second degree relative with history of ovarian cancer
First degree relative with history of breast cancer diagnosed before age 50
Two or more first or second degree relatives with history of breast cancer at any age
Personal or any first or second degree relative with bilateral breast cancer
History of breast cancer in male relative

Scientists have worked hard to identify other genes that a woman might inherit that increases her susceptibility to breast cancer. It is very obvious that there are no other genes that, if abnormal, have the kind of strength that BRCA1 and 2 have to cause a woman to develop breast cancer. Rather, we now believe it is likely that most women who get breast cancer have two or more genetic abnormalities (more precisely put, differences from other unaffected women rather than an abnormality) that by themselves don’t do much. However, when present in the same individual who is then exposed sufficiently often to external factors that might cause the disease, she is more likely to get breast cancer.

The hunt for these genes has been exceedingly frustrating. Many “candidate” genes (that is, knowing what they do in the normal setting that suggests that they might, logically, result in cancer if abnormal) have simply not panned out as risk factors in epidemiologic studies. However, a recent reported study regarding a mammoth effort by many highly experienced experts in the field has suggested that there might be four genes that are new “candidates.” Intensive study of these candidates will be the focus of future research.

Prevention of Breast Cancer

Understanding the cause and risks of breast cancer might lead to strategies to prevent it. Unfortunately, as noted, there is no single common cause of breast cancer that can be altered, as there is with lung cancer, and there are no known life-style changes that have been proven to lower breast cancer risk. Nonetheless, there are some strategies that have been shown to be effective.

Prophylactic Surgery^{2, 3}. Prophylactic surgical removal of unaffected breast tissue (prophylactic mastectomy) appears to reduce the risk of getting a new breast cancer considerably. Due to ethical concerns, there has never been a prospective randomized clinical trial asking whether removal of breasts from otherwise normal women actually prevents breast cancer. However, retrospective and prospective monitoring studies do suggest that this is the case. This statement seems intuitively obvious, but it must be understood that the breasts are not encapsulated organs, like the kidneys, and breast tissue is diffusely distributed under the skin. Therefore, except for the most aggressive surgeries, most prophylactic mastectomies leave behind some breast tissue, which can always become malignant. Nonetheless, these studies show that prophylactic mastectomies appear to reduce the risk of getting a new breast cancer by almost 90% of whatever a woman’s risk was before the surgery. These same studies suggest breast cancer mortality is also decreased by about the same amount.

For most women, prophylactic mastectomy is unacceptable, and it is not recommended by most surgeons except for those patients with very high “genetic” risks, (in other words, women who are BRCA1 or 2 “positive”). Indeed, for a woman with average or slightly elevated risk, the adverse cosmetic and emotional aspects of this aggressive approach outweigh the small potential benefit.

Disruption of the estrogen/estrogen receptor system^{4, 5.} As noted, approximately two-thirds of all new breast cancers appear to be driven by estrogen binding, and activation of the estrogen receptor. It has been known for years that young women with either natural or surgical premature menopause have lower risks of breast cancer than women whose menopause occurs around 50 years. However, as with prophylactic breast removal, prophylactic surgical removal of a young woman’s ovaries is associated with substantial social, sexual, and emotional difficulty. Of course, it ends any prospects of fertility. However, even if a woman has elected not to have any more babies, early menopause (less than 40 years) also appears to increase the risk of non-breast cancer medical problems, such as osteoporosis and cardiovascular disease. In fact, a recently published study from the Mayo Clinic demonstrated that woman who had their ovaries removed before age 35 had shorter life expectancy than those who went on to have natural menopause.

Rather than surgery, women can also use medical means to interrupt the estrogen/ER system. This strategy has become known as “chemoprevention.” Chemoprevention should not be confused with “chemotherapy,” which is used to treat established breast cancers after they are diagnosed, and will be discussed later. The most widely studied approach so far is the use of medicines that bind to the ER, just like estrogens. These medicines are called “Selective Estrogen Receptor Modulators” (or “SERMs” for short). Tamoxifen (Novadex™) is the oldest and most widely used of these. As we will discuss below, for the last 40 years, tamoxifen has been the mainstay of treatment of women with breast cancers that make ER. Several large, prospective randomized clinical trials (the best kind of studies) have shown that daily tamoxifen for five years reduces the risk of getting a new breast cancer by nearly one-half in women who are at moderately high risk for, but who have never had, breast cancer. Not surprisingly, tamoxifen only prevents those cancers that need estrogen (ER “positive”) and does not affect the incidence of ER negative cancers.

SERMs, such as tamoxifen, are odd medicines, reacting different ways in different cells. As a general matter, they enter all cells, but they will affect those cells that make estrogen receptor. In such cells (ER positive cells), SERMS bind the ER, so they prevent estrogen from doing so. The ER, now bound to the SERM, goes to the nucleus of the cell just as if it were bound to estrogen. In some tissues, like breast and brain, the ER-SERM combination prevents the cell from functioning, in other words in these tissues the SERM is “anti-estrogenic.” This is why tamoxifen works against ER positive breast cancers. Since the same effect occurs in the part of the brain where body temperature is controlled, and since estrogen seems to stabilize body temperature, the anti-estrogenic effects of tamoxifen frequently cause women to have hot flashes.

However, in other tissues that also need estrogen, like bone, liver, and uterus (the womb), SERMS can actually act like estrogen! Thus, tamoxifen prevents osteoporosis (bone thinning) just like estrogen does, and, like estrogen, causes the liver to make too much of the proteins that cause blood clotting. Also like estrogen, tamoxifen causes the lining of the uterus (called the endometrium) to expand, and can even cause cancer of that tissue. Women who take tamoxifen (or for that matter, estrogen, as well) are more likely to have blood clots and also to develop uterine cancers, although not very much more likely.

Scientists have tried to identify other SERMs that might be preferable to tamoxifen. One of these, raloxifen (Evista®), has been compared directly to tamoxifen as a preventive agent in a prospective randomized clinical trial of higher risk women. In this study, raloxifene was a little less effective in preventing cancers, but also a little less likely to cause blood clots. Raloxifene does not appear to affect the uterus at all, so it does not increase the risk of endometrial cancer. Raloxifene has already been proven to prevent osteoporosis compared to placebo, and it is approved by the FDA for this use. It is not known whether raloxifene is better or worse than tamoxifen for this use.

So far, widespread acceptance of either of these agents to prevent breast cancer has been limited, in part due to the annoying side effects (like hot flashes and sexual difficulties) and occasional life-threatening toxicities (like blood clots or uterine cancers). It has not been shown that use of these agents results in reduction in mortality, partly because even “high risk” women, other than those few with genetic risk, are not terribly likely to die of breast cancer over a 5-10 year period of time, and perhaps because SERMs are mostly preventing the cancers we are most likely to cure anyway.

These considerations highlight that we need better ways to medically prevent breast cancer. Some research on preventive mechanisms has come from observations of postmenopausal women who have been diagnosed with ER positive breast cancer. In this group, several prospective randomized clinical trials have shown that completely preventing estrogen production is slightly more effective than tamoxifen in preventing a recurrence of that cancer (this strategy will be discussed below in TREATMENT OF BREAST CANCER: Systemic Therapy). Even postmenopausal women make some estrogen, but not from their ovaries, as do younger women. Rather, older women make a precursor of estrogen in their adrenal glands (the same glands that make adrenaline), and this precursor is converted to estrogen in other cells (mostly fat cells). This is the equivalent of an oil well (the adrenal glands) making crude oil and the refineries (the fat cells) converting it into gasoline. This conversion is performed by a protein in the fat cells called an aromatase. Three drugs that inhibit aromatase function have been approved by the FDA to treat women with established breast cancer. In addition to preventing recurrences in women who have ER positive breast cancers, all three appear to also prevent new breast cancers in those women who have another breast. Prospective randomized clinical trials comparing these to placebo or to a SERM to prevent breast cancer in high risk women who have never had breast cancer are either underway or planned. Since these agents are pure anti-estrogens, they have some of the same but also different side effects and toxicities. Like the SERMs, they cause hot flashes and sexual difficulties. However, they actually increase the risk of osteoporosis, while not causing blood clots or uterine cancers. They also cause a common complaint of joint aches and pains, which in approximately 10-15% of women can be quite severe. It is not recommended that a woman without breast cancer take any of these aromatase inhibitors for prevention, outside of a clinical trial at this time.

We still do not have any good, safe, and effective measures, other than surgery, to prevent ER negative cancers. This is an area of active research in many laboratories, but currently nothing has been very promising in clinical trials.

Screening for Breast Cancer^{6, 7}

There is no other cancer for which screening has been as carefully studied as breast cancer. Beginning in the late 1960s, nine prospective randomized clinical trials, involving over 100,000 women, have examined whether screening mammography, with or without a clinical breast examination by a trained professional, decreases the risk of dying of breast cancer. Of course, screening will not prevent a new breast cancer. Rather, these studies were performed based on the concept that early detection of an existing cancer results in earlier, and therefore more effective, treatment. Initially, early treatment involved solely treating the breast with surgery and possible radiation. These are called “local treatments,” meaning they only treat the local area where the cancer began. On the other hand, “systemic” treatments, such as anti-estrogen therapy, chemotherapy, and more recently anti-HER-2 therapies, go throughout the body (all through the “system”). Several prospective, randomized, controlled trials (PRCTs) have demonstrated that early application of these treatments is much more effective in preventing mortality than waiting until the cancer metastasizes outside of the breast, such as to the bones, lung, or liver. Several studies have shown that we rarely, if ever, cure patients with metastatic breast cancer, so early detection and treatment are very important.

The results of the nine PRCTs of screening mammography have generated considerable controversy through the years. Although most have demonstrated mortality reductions for those women who are screened, not all have. However, when all of the studies are pooled together, it appears that routine screening reduces breast cancer mortality in women over 50 (those most likely to get it) by approximately one-quarter to one-third. However, in many respects, these studies were over-interpreted by well-meaning doctors and lay persons to mean that screening would eliminate breast cancer deaths, which is not the case. They have also been cited to recommend that every woman should be screened-even young women less than 40 years. Other scientists have said that the “positive” studies – those that showed a benefit to screening -- were not well done, and that careful evaluation fails to demonstrate any benefit.

As of this time, much of this controversy has been laid to rest in standard clinical practice in developed countries in which breast cancer is a major health risk. In general, most expert panels that make recommendations for doctors suggest that women should begin screening mammography in their 40s and continue it until at least 70 years of age, and perhaps longer, if they are otherwise healthy and treating breast cancer, if they developed it,would be rational.

Regardless, mammography is not perfect, by any means. As noted, screening studies have only demonstrated a reduction in mortality of 25-35%. This implies that 65-75% of women who die of breast cancer will do so in spite of screening. Screening mammography only detects approximately 80-90% of all cancers; in other words, it misses around 10-20%. It is also frequently falsely positive. Up to 75% of “positive” mammograms (positive means that an abnormality is found that requires a biopsy) are not cancer.

Can we do better than screening mammography? No single modality has been shown to be better than mammography. Breast ultrasonography is widely used to help define abnormal mammograms and make them more specific, thus decreasing unnecessary biopsies. However, routine screening ultra-sonography in women without a mammographic finding has not been found to be very helpful. Recently, magnetic resonance imaging (MRI) of the breast has been intensively studied and has resulted in considerable controversy. There is no question that breast MRI is more sensitive than mammography, detecting 90-95% of all cancers. However, several (but not all) studies have demonstrated that screening MRI is less specific, so that it detects more abnormalities that require biopsy but are not cancer. MRI is also much more expensive than mammography. Currently, it seems reasonable to perform routine screening MRI in women who are otherwise considering prophylactic mastectomy but are not ready to do so, and in women with particularly dense breasts for whom mammography is notoriously insensitive.

Many other modalities to screen for breast cancer have been studied or proposed. However, none has been put to the kind of testing that mammography has, in particular PRCTs looking to see if breast cancer mortality is reduced. Many of these are like MRI-- more sensitive, but without an indication of specificity, such that using them turns up more false positive results. This may cause more harm than good by resulting in unnecessary surgeries and anxieties.

Treatment of breast cancer

It is helpful to think of breast cancer as a continuum from what is often termed “early” breast cancer to “advanced” or “metastatic.” Early breast cancer usually implies that the cancer is only detectable in the breast and surrounding lymph nodes, particularly in the axilla (the arm-pit). Doctors have divided early breast cancer into three stages, I, II, and III, so that they can communicate more readily and consistently with each other in a type of short-hand (See Table 3 for a brief description of the so-called TNM staging system, which is based on the size of the primary Tumor (T), the status of the axillary lymph Nodes (N), and whether there are or are not distant Metastases). In stage I breast cancer, the actual cancer in the breast (called the “primary” cancer) is small (less than 2 centimeters [cm]) and no cancer can be found in the axillary lymph nodes. Stage II primary cancers are either bigger (2-5 cm) and/or there is some involvement of the axillary lymph nodes. Stage III breast cancers are larger than 5 cm, have extensive axillary nodal involvement, and/or have certain worrisome findings on physical examination, such as redness, nodules, or ulceration of the skin, or suspicion the cancer is fixed to the muscle and bones beneath the cancer site. If the cancer can be found outside the breast and axillary lymph nodes, it is called metastatic, which is designated stage IV. Metastatic breast cancer is most often found in the bones, liver, lung, or lymph nodes outside the axilla, although it can occur in any organ. Even though it is growing in these organs, it is still considered breast cancer; when breast cancer spreads to the bone, for example, it is not bone cancer, so its treatment follows breast cancer protocols, which are different from primary bone cancer protocols.

These days, due in great part to intensive screening programs in the US and other developed countries, most patients are diagnosed with stage I-III disease. Only 5% of patients present with metastatic breast cancer at diagnosis. The odds of developing metastatic, or stage IV, breast cancer over the next 5-10 years after diagnosis of breast cancer are directly linked to the initial stage. In other words, although at time of diagnosis we cannot find metastatic cancer in other organs, very small deposits of cells (called micro-metastases) must have already left the primary cancer and spread to these sites.

Breast cancer is not one disease. Rather, there are several types of breast cancers, and these can be distinguished by a pathologist looking at the cancer under a microscope and by special testing of the cancer. Breast cancer starts in the milk glands, or ducts, and often remains confined to these ducts without any evidence of invading surrounding normal tissue. This kind of breast cancer is called intra-ductal breast cancer, or more commonly ductal cancer in situ (DCIS), which means it has stayed in the place it started. DCIS is really a pre-malignant condition, since if that is all a patient has, there is little or no chance the cancer has sent out micrometastases. If the cancer has broken out of the duct, it is called “invasive” or “infiltrating” cancer. This is the kind of cancer that is able to get into the lymph and blood vessels of the breast and travel to other sites, ultimately causing metastases.

Pathologists can also provide an estimate of how likely it is that an invasive cancer may have spread. One way is to determine if the cancer has spread to the axillary lymph nodes or not. We know that a patient with positive axillary lymph nodes has about twice the risk of developing subsequent detectable metastases than a patient with negative lymph nodes. The likelihood of developing metastases is called “prognosis.” The size of the tumor is also prognostic (hence the importance of size in the staging system discussed above), as is the tumor grade. Tumor grade is determined by an experienced pathologist who can tell under the microscope if the cancer looks like it is likely to be well or poorly behaved. Grading is based on three components: 1) does the cancer cell nucleus look bad; 2) are the cancer cells trying to make glands (worse prognosis cancers don’t make glands; rather the cells just organize in sheets); and 3) how many of the cancer cells are dividing within the microscopic field (worse cancers are dividing more rapidly). Grade is provided as I (favorable), II (intermediate) and III (poor). In addition, there are a few so-called special types of breast cancers that seem to have a particularly good prognosis, including tubular, mucinous, and colloid cancers. Additional testing of the cancer can also help to determine prognosis. Cancers that make estrogen and progesterone receptor are less like to cause metastases, especially in the first several years after diagnosis, but HER-2 positive cancers have a worse prognosis.

There are fundamentally two types of treatment for breast cancers: 1) Local treatments, which are strategies that only treat the cancer in a single region of the body, such as the primary site; and 2) systemic treatments, which are usually given orally or intravenously and go all through a patient’s “system.” Local treatments include surgery and radiation, and occasionally other locally-applied therapies such as heat therapy. Systemic treatments include anti-estrogen treatments, chemotherapy, and more recently treatments directed towards the HER-2 molecule and treatments directed towards blocking new blood vessel growth, called angiogenesis inhibitors. Overall treatment of any patient with breast cancer often requires doctors trained in the three different methods of therapy: surgeons, radiation oncologists, and medical oncologists-this type of approach is called “multi-disciplinary treatment.”

Primary Treatment of Breast Cancer

Primary Surgery8, 9. For women with stage I-III breast cancer, treatment of the primary cancer is of paramount importance. Beginning in the late 1890s, led by Dr. William Halsted and others,surgeons developed the theory that breast cancer spread in a logical fashion from the breast to the surrounding lymph nodes and then, after a period of time, to the rest of the body. Therefore, they presumed that the more local treatment that was applied, the more likely the patient would be cured. This theory led to the “Halsted Radical Mastectomy,” in which not only the breast but underlying muscle tissue were removed, as well as most if not all of the lymph nodes in the axilla. Later, radiation to the chest wall was added to augment the radical mastectomy.

In the 1940s and 1950s, doctors began to question the Halsted theory, and wondered if less aggressive local therapy, such as doing less surgery and/or not giving radiation, might be as effective as the Halsted Radical Mastectomy followed by chest wall radiation. Prospective randomized clinical trials over the ensuing 3 decades demonstrated that for approximately 60% of women with stage I-III breast cancer, performing breast “conserving” therapy works just as well as doing a mastectomy. Follow-up of these studies for more than 30 years confirms that long-term survival for women treated with breast conserving therapy is the same, or even better, than those who had a mastectomy. Breast conserving therapy involves removing the primary cancer from the breast (also called a “lumpectomy,” “wide excision,” “partial mastectomy,” or “quadrantectomy”) while leaving the rest of the breast intact. Breast conserving therapy is usually delivered as complete removal of the cancer followed by radiation to the breast. However, the value of the radiation has been questioned. Prospective randomized clinical trials of breast conserving surgery with or without radiation were found to result in an unacceptably high rate of recurrences in the breast. Therefore, currently, for most women, breast conserving treatment involves both surgery and radiation. There is at least one prospective randomized clinical trial that suggests that the radiation might not be needed in older (>65 years) women with ER positive and node negative breast cancers that are less than 2cm, but many doctors are not willing to eliminate the radiation even for this group of women until followup in this trial is much longer.

Still, there are some patients for whom mastectomy is a better treatment option. Doctors have found that if the primary tumor cannot be completely excised, the risk of having the cancer come back in the breast is unacceptably high, even with radiation after the surgery. Thus, women with large tumors and especially small breasts usually are better treated with mastectomy, since a complete excision requires removal of most of the breast anyway. Some of these women can have breast conserving treatment if they receive systemic treatment first, to shrink the cancer. This will be discussed in greater detail below. Other reasons to perform a mastectomy instead of breast conserving therapy include finding cancer at the edge of the excised tissue (this is called a positive margin), and if there are multiple cancers in the same breast, either as discrete separate cancers or evidence that the cancer is in many places. A common reason for recommending mastectomy is evidence of wide-spread DCIS, which can be presumed by mammographic finding of worrisome calcification throughout the breast once a tissue diagnosis of DCIS is made.

Most doctors also recommend mastectomy for women who initially are found to have inflammatory breast cancer, which is a special type of cancer that makes the skin of the breast look red (or “inflammatory.”). This kind of cancer is especially aggressive, Efforts at breast preservation in women with inflammatory breast cancer (often called “IBD”) have resulted in very high risks of local recurrence, so these patients are usually treated with mastectomy and radiation to their remaining chest wall and surrounding lymph nodes. Finally, there are some women for whom radiation is dangerous, and therefore they are better served with mastectomy. These include women with certain skin conditions, such as systemic lupus erythematosus, and women who have previously had radiation to the breast. The latter is most often seen in women who have had been treated for Hodgkin’s disease with radiation to their chest, or women with a prior breast cancer who were treated with breast conserving therapy.

Examination of the axillary lymph nodes10, 11{Veronesi, 2003 #7858}.

At the time of primary breast surgery, most women have some sort of evaluation of their axillary nodes, to determine whether the cancer has spread there. This is done for several reasons, mostly related to determination of prognosis and subsequent direction of therapy. For example, most women who have positive axillary lymph nodes will receive radiation therapy to that area after surgery, while those with negative axillary lymph nodes may not. Likewise, systemic therapy decisions are often based on the presence or absence of lymph node involvement. As noted, Halsted and his followers believed that radical dissection of the axilla was an important component of breast cancer treatment, and women often had 50 to 60, or more, lymph nodes removed at the time of mastectomy. These surgeries were frequently followed by horrible complications, including massive swelling of the arm on that side because the normal drainage patterns from the arm were disrupted (this condition is called “lymphedema”). In the 1980s, data suggested that such radical dissections were not needed, and so only 10-15 lymph nodes were removed or “sampled.” Since the mid-1990s, several studies, and even a few prospective randomized trials, have demonstrated that just removing the first lymph node that drains the breast, called the “sentinel node,” may be sufficient (note: sometimes there are a few sentinel lymph nodes rather than just one, and they are all removed). If the sentinel node does not have cancer in it, it is very unlikely that any of the other axillary lymph nodes are positive, and so there is no reason to remove them. If the sentinel node is positive, the standard of care at this time is to proceed with axillary sampling (10-15 extra nodes) to determine the number of involved lymph nodes. There is even controversy about the benefit of taking out positive nodes. Some studies suggest that removal of positive nodes decreases the risk of subsequent recurrences in the axilla, while others suggest that radiation can replace surgery, and that long-term survival is not affected. However, the current standard of care for a woman with a positive axillary lymph node is further axillary lymph node resection.

Radiation^{12, 13}.

For women undergoing breast conserving therapy in the U.S., breast conserving radiation therapy has been classically given to the entire breast over approximately 6 weeks, followed by a “boost” to the specific site of the primary for approximately 2 more weeks, for a total of 8 weeks of radiation therapy. However, recent studies have suggested that perhaps only the site of the primary cancer needs to be treated, which is called partial breast radiation. Partial breast radiation can be given either from the outside, the way that classic radiation is delivered, or it can be given by inserting radioactive material into the cavity that is left after the primary breast cancer has been removed. The potential advantage of partial breast radiation is that less normal tissue is exposed to radiation. However, this approach is relatively new and it is not clear that it is as safe or as effective as classic radiation. Prospective randomized clinical trials comparing the two methods are now underway.

Outside of the U.S., such as Canada and the U.K., both whole breast and partial breast irradiation is given over a shorter time periods, from 3-4 weeks, to even just a few days. This “short-course” radiation could be preferable, since it saves time for the patient and resources for the medical community. Large randomized trials of whole breast irradiation given in the classic fashion or short-course suggest that the latter is as safe and effective at the former. At present, it has not been widely adopted in the U.S., mainly out of concern that followup may not be sufficiently long to be certain that the efficacy and cosmetic outcomes are not worse. Short course, partial breast radiation is still under investigation.

If a patient has a mastectomy, she may still need radiation. Prospective randomized trials have demonstrated that radiation to the remaining chest wall tissue reduces the chances of recurrence in that area (called “local recurrence”) by 60-75% of whatever the initial risk would have been. These same trials also showed a 25-30% reduction of systemic metastases in those patients who received chest wall radiation, and even longer survival. Therefore, it is common practice to recommend radiation to patients with a high risk of local recurrence: larger tumors (>5cm), positive margins in the mastectomy specimen, and multiple (4 or more) positive axillary lymph nodes. Most doctors agree that radiation should not be given to women with small tumors (<2cm), negative margins, and negative nodes. There is controversy about whether radiation should or should not be given to women with either 2-5cm tumors or 1-3 positive nodes. Women who have had inflammatory breast cancer are always treated with radiation after mastectomy.

Regardless of whether a patient has breast conserving therapy or mastectomy, radiation to the surrounding lymph node regions is usually recommended if she has 4 or more positive nodes, and often if she has 1-3 positive nodes.

Table 2.  Primary Therapy of Breast Cancer

Therapeutic approach	Therapy Required	Best Patients
Breast Conserving Therapy	Surgical excision of entire cancer Radiation to breast	Single tumor in breast, involving <5cm Not inflammatory, or with evidence of skin or chest wall involvement Margins negative after surgery No reason patient cannot receive radiation
Breast Conserving Therapy	Surgical excision of entire cancer NO radiation	Not yet clear. Best data currently supports selected women >65 years old with ER positive tumors <2cm and negative axillary nodes who receive adjuvant anti-estrogen therapy
Mastectomy	Surgical removal of breast with tumor.	Patients who are not candidates for BCT (see above) Patients who prefer mastectomy Patients who wish to avoid or cannot receive radiation
Mastectomy and Chest Wall Radiation	Surgical removal of breast with tumor Radiation therapy to chest wall after surgery	Tumor >5cm; or Positive margins after mastectomy; or >3 axillary lymph nodes involved with cancer   Consider: tumor 3-5 cm and/or 1-3 involved axillary lymph nodes.

Reconstruction^14-16

For women who elect or require mastectomy, plastic surgery to reconstruct the breast is a reasonable option. The technology to perform reconstruction has advanced remarkably over the last two decades. Reconstruction can be performed in one of many ways. Silicon or saline implants (basically bags filled with the solution) can be used to reconstruct a breast, or a patient’s own tissue can be moved from her abdomen or back to her chest. The former is usually considered an easier operation, but the latter is usually cosmetically superior. Nipples and areola can be added with extra tissue and tattooing. The optimal approach for any woman is complex and requires many considerations.

There are a few considerations for reconstruction. Many women elect to have “immediate” reconstruction, which means the procedure is started during the same operation as the mastectomy, with the oncologic and plastic surgeons working in tandem. However, if you are going to have chest wall radiation, most plastic surgeons prefer to delay reconstruction until after the radiation is completed. You should also understand that reconstruction does require a major surgery and often several subsequent other operations. Furthermore, because the mastectomy removes nerves, the skin of a reconstruction is usually numb, and of course the nipple, if added, is insensitive to any stimulation and will not become erect. Many women are afraid that reconstruction will hide a recurrence, but this has not been the case with long followup.

In summary, reconstruction can be very successful in helping restore at least cosmetic integrity to a woman after a mastectomy. A recent study has suggested that many women are never even offered the opportunity to consider plastic surgery after a mastectomy. If you are going to have a mastectomy, and if you are interested, be certain you discuss the issue with your surgeon and that you are referred to an experienced plastic surgeon so you can make well-informed decisions.

Systemic Therapy

Systemic treatments have improved immensely over the last two decades. Indeed, treatment options for patients who have developed metastatic breast cancer have more than doubled since 1980, and the lives of most patients with metastatic disease are improved greatly. However, sadly, patients with metastatic breast cancer are rarely if ever cured-in other words, currently available therapies almost never make the cancer go away and never return.

Nearly 50 years ago, clinical scientists wondered whether it might be more effective to treat patients with systemic therapies before their cancer grew into detectable metastases, rather than waiting for these recurrences to occur. Such a strategy is called “adjuvant” systemic therapy, which means starting such therapy while the cancer is still in its “seed” or micro-metastatic phase. Indeed, many prospective randomized clinical trials have consistently shown that adjuvant therapy is much more effective in improving survival than delaying therapy until, and if, a patient develops metastases.

Prognosis and Prediction^{17, 18}

One of the greatest challenges for any patient with newly diagnosed breast cancer is to determine her likelihood of developing metastases (after all, you would not want to take therapy you did not need). Doctors call the likelihood of recurrence “prognosis.” A second challenge is to estimate the likelihood that a given systemic therapy will work (after all, you would not want to take therapy that does not work). Doctors call the likelihood of a therapy’s working “prediction.”

As discussed earlier, prognosis is currently based on clinical and pathological staging, especially the axillary lymph node status, as well as estimates of tumor grade and ER, progesterone receptivity (PgR), and HER2 status. Adjuvant systemic therapy is almost never recommended for a patient with DCIS, although such patients might take tamoxifen or raloxifene as preventive therapy against a new, second primary cancer in the other breast. However, almost all women with invasive breast cancer have a reasonably high risk of subsequent recurrences, and so all such women should meet with a medical oncologist to discuss the risks and the benefits of adjuvant therapy. These factors can be plugged into an online mathematical calculator, called Adjuvant! http://www.adjuvantonline.com/index.jsp, which provides an estimate of the chances of developing metastases over a ten-year period of time if the patient receives no adjuvant systemic therapy.

As noted above, in addition to being prognostic factors, ER and HER2 are also important predictive factors to determine if certain kinds of systemic therapy will or will not work. Cancers that do not make ER (“ER negative”) are not sensitive to anti-estrogen therapies, and therefore this strategy is not used in such patients. Cancers that do not make HER2 do not appear to respond to anti-HER2 therapies, such as trastuzumab (brand name, Herceptin®) and, likewise, these treatments are not recommended for patients with HER2 negative cancers. At present, there is no good predictor for whether chemotherapy will work or not. Recent studies have suggested that cancers that are ER positive, HER2 negative, and have low (favorable) tumor grade may be less likely to respond to specific types, or even all, chemotherapies. However, these studies are preliminary and most doctors do not feel they should be used yet to decide whether a patient with a relatively poor prognosis (for example with positive nodes) should receive chemotherapy.

Lately, scientists have developed assays that combine the expression of many different genes (in other words, are these genes “turned on” or not) at once in the same cancer in order to try to improve the estimate of a patient’s prognosis and perhaps even to predict whether chemotherapies will be effective. These exciting studies are very promising, but they are quite new and for the most part it is not entirely clear how to use these assays. However, one of them, called OncotypeDX™, at least appears to permit identification of women with particularly favorable prognosis if they have ER positive cancers and negative axillary nodes. In fact, their prognosis appears so good that, even if chemotherapy worked, the number of women who could benefit is so low that it is balanced by the number of women who have life-threatening toxicities. Therefore, OncotypeDX™ has been recommended for use in such patients to help decide if they might wish to forego therapy to avoid toxicities.

Table 3. Commonly Used Prognostic and Predictive Factors for Breast Cancer

Factor	Prognostic?	Predictive	If Predictive, for What?
Clinical findings of advanced stage (called T4):          Inflammatory changes          Skin involvement          Fixation to the chest wall	Yes	No
Lymph nodes involved with cancer          Num Pos          Staging          0                       N0          1-3                   N1          4-9                   N2          >9                    N3	Yes	No
Size of primary cancer          Size                  Staging          <2cm                T1          2-5cm               T2          >5                    T3	Yes	No
Estrogen Receptor & Progesterone Receptor	Yes Positive is favorable	Yes Positive predicts benefit	Anti-estrogen therapy       Ovarian ablation       Tamoxifen       Aromatase inhibitors
HER2 (also called erbB2 and c-neu)	Yes Positive is unfavorable	Yes Positive predicts benefit	Anti-HER2 therapy       Trastuzumab       Lapatinib
Multi-factor assays (measure many at  once)          OncotypeDX®                (Recurrence score, RS)                Mammaprint®	Yes in Node negative, ER positive patients Low RS is favorable Yes	Maybe Low RS predicts lack of benefit     Unknown	Chemotherapy

 

Adjuvant Systemic Therapies^19-21

Once a decision has been made to treat a patient, the second decision, identifying the best therapy, is based on predictive factors.

Anti-estrogen therapies. As noted ER is a powerful predictor of the benefit of adjuvant anti-estrogen therapy. It has been estimated that five years of adjuvant tamoxifen reduces the risk of recurrence by nearly one half for women with ER positive breast cancers over a ten-year period of follow-up. Therefore, if a patient has a 20% risk of metastases, taking tamoxifen decreases her risk to nearly 10%. Nearly 10% of such patients appear to be cured because of the tamoxifen. Although tamoxifen has been the mainstay treatment for ER positive patients there are several other anti-estrogen therapies. These include either removing ovaries, or stopping their function by medical treatment, in women who are still having menses. These treatments are called “ovarian ablation.” Ongoing studies are addressing whether premenopausal women should only receive tamoxifen, or if they should have ovarian ablation and then receive tamoxifen or an aromatase inhibitor (AI).

For post-menopausal women, several recently published prospective randomized clinical trials have demonstrated that the aromatase inhibitors are slightly more effective in reducing cancer recurrence than tamoxifen. However, it is not known if they should be given instead of tamoxifen, or after 2-5 years of tamoxifen, or perhaps for a few years before tamoxifen is given. There are three aromatase inhibitors on the market: anastrozole (Arimidex™), letrozole (Femara™), and exemestane (Aromasin™). Currently, none of these appears to be superior to the others with respect to activity or side effects. Prospective randomized clinical trials are underway in pre-menopausal women, comparing tamoxifen alone to ovarian ablation plus tamoxifen, or to ovarian ablation plus an AI, and in post-menopausal women comparing the AIs with each other.

The side effects of these agents are fairly predictable based on their mechanisms of action. As previously discussed, tamoxifen (Nolvadex™) is a SERM, and as such it has anti-estrogenic activity in breast, brain, and commonly vagina, but estrogenic activity in bone, liver, and uterus. Thus, tamoxifen very commonly causes hot flashes (anti-estrogenic effect in brain) and sexual difficulties such as pain with intercourse (anti-estrogenic effect in vagina). On the other hand, tamoxifen actually decreases osteoporosis (estrogenic in bone). It increases the risk of blood clots (which can result in thrombosis in the large veins in the leg and in strokes) because of its estrogenic effect in liver and it increases the risk of cancer of the womb (the endometrium) because of its estrogenic effect in that tissue. It is important to note that this risk is not in any way related to cervical cancer. Pap smears are important to screen for cervical cancer in any sexually active woman, but they do not screen for any tamoxifen-related cancer. Indeed, routine screening (for example with trans-vaginal ultrasonography) for endometrial cancer is not recommended, since the actual risk of endometrial cancer in a woman on tamoxifen is not really very high (it is simply that it is higher than that for a woman not on tamoxifen) and the false positive rate of other non-malignant but confusing findings for women on tamoxifen may be as high as 20%.

There are a few important caveats for women considering tamoxifen. First, it should be noted that tamoxifen and raloxifene (Evista™) are very similar drugs. If a woman develops breast cancer while taking raloxifene, either for osteoporosis or to prevent breast cancer, she should not be treated with tamoxifen, since it is very unlikely it would work, and vice versa. Likewise, a patient should not take both drugs together (some doctors might mistakenly recommend tamoxifen for breast cancer and raloxifene for osteoporosis). Also, it has been known for years that tamoxifen itself is only a weakly active drug. Rather, it appears to need to be converted to one of two metabolites to really be active. The protein, also called an enzyme) in our bodies that is responsible for this conversion is called CYP2D6. Recently reported data suggest that up to 10% of women of European descent have inherited a faulty copy of CYP2D6, and therefore they cannot convert tamoxifen to endoxifen nearly as well as those women who have the “normal” (or most common, which is also called the “wild type” version) gene. In these women, tamoxifen does not appear to be as active in their bodies. Studies are ongoing to determine whether these women should be treated with anti-estrogenic strategies other than tamoxifen. It has also been found that even if a woman has inherited normal CYP2D6, there are certain drugs that inhibit its activity, and these should not be taken by women who are prescribed tamoxifen. Ironically, these include certain medicines that are often used to treat hot flashes, in particular paroxetine (Paxil™) and fluoxetine (Prozac™). A brochure that describes these potential interactions, and which drugs should be avoided, can be found at http://medicine.iupui.edu/clinical/PG_frames.html .

All three AIs, on the market: anastrozole (Arimidex®), letrozole (Femara®), and exemestane (Aromasin®) are pure anti-estrogens. They all seem to be equally active, and they seem to have similar side effects. As anti-estrogens, they cause hot flashes and vaginal dryness/sexual problems, but unlike tamoxifen they increase osteoporosis. They do not increase blood clotting or endometrial cancers, since they have no estrogenic properties. AIs do not work in premenopausal women, and so women having periods should not be treated with an AI. Even women who have previously been pre-menstrual but who have quit having periods due to adjuvant chemotherapy should not receive an AI, since these drugs can actually reactivate (or wake up) a “sleeping” ovary, resulting in exactly the opposite of the intended effect. Postmenopausal women taking AIs should be monitored for osteoporosis and should take daily calcium and vitamin D. Some of these women who have progressive osteoporosis will need to take specific therapies, called bisphosphonates, for this condition. A large prospective randomized trial demonstrated that women who took a combination of tamoxifen and anastrozole (Arimidex™) actually did worse than women who only took anastrozole, and so these drugs should not be used together. Likewise, raloxifene (Evista™) should also not be used with an AI.

One of the most common complaints, and indeed the most common reason that women quit taking AIs, is a syndrome of aches and pains in the joints and bones. This so-called “musculoskeletal” syndrome occurs in up to 40% of women taking AIs, and two recent studies have demonstrated that 10-15% of women quit taking the drug because of it. The symptoms can be treated with non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, but sometimes these just are not successful. The cause for this syndrome, and the reason some women get it and others do not, is not clear, but it must be distinguished from recurrent, bone metastases.

Chemotherapy

Chemotherapy has been used to treat breast cancer since the early 1960s. Chemotherapy works in many ways, but basically it targets cells that are dividing rapidly. Therefore it is not as specific as anti-estrogen or anti-HER2 therapy and has more side effects. Large randomized trials have demonstrated that overall chemotherapy reduces the chances of distant metastases by approximately 30%. Thus, using Adjuvant! you can calculate that if a patient has a 50% chance of recurrence over ten years, she might lower her risk by approximately 15% (roughly 1/3 of 50%), to 35%. Generally, approximately 1-2% of all women who receive chemotherapy in this country will suffer a life-threatening toxicity, such as infection, bleeding, a second malignancy, or heart damage. Thus, most oncologists strongly recommend adjuvant chemotherapy to women for whom a more than 5% absolute benefit is calculated, and not to women for whom the calculated chance of benefit is only 1-3%. It is not clear whether chemotherapy should be routinely recommended for women with a calculated absolute benefit of 4-5%, and indeed there is an ongoing prospective randomized clinical trial in North America addressing just this issue.
A common misperception is that the choice of primary breast therapy (breast conservation vs. mastectomy) might influence whether or not a patient should receive chemotherapy. This is not true. The decision to use chemotherapy or not is based on the risk of distant metastases, and is not in any way reduced if a patient elects to have a mastectomy. Thus, the primary therapy decision should not be made in hopes of avoiding chemotherapy.

Many types of chemotherapeutic agents are active in breast cancer. The most commonly used are cyclophosphamide (Cytoxan®), methotrexate, 5-fluorouracil, the anthracyclines: doxorubicin (Adriamycin®), epirubicin (Ellence®), and the taxanes: paclitaxel (Taxol®) and docetaxel (Taxotere®). It is important not to confuse the latter with tamoxifen. Chemotherapy agents are frequently combined into regimens that are identified by the first letter of each drug; for example, CMF, CAF, AC, AC-T, TAC, EC, EC-T, etc. Several studies have shown that the addition of either doxorubicin or epirubicin, which are called anthracyclines, is slightly better than regimens without them, especially CMF. This observation may be particularly true for women who have HER2 positive breast cancers, while, for example, CEF appears to be the same as CMF for those with HER2 negative breast cancers. The addition of a taxane also appears to further improve the odds of not recurring. A large randomized clinical trial comparing paclitaxel and docetaxel has suggested that the activities of the two taxanes are very similar. Several studies have been completed or are ongoing to determine if addition of a taxane might make the use of an anthracycline unnecessary, and therefore avoid the higher risk of secondary leukemia (a new cancer of white blood cells) and congestive heart failure, both of which are known complications of anthracyclines. However, at present this approach remains controversial, especially for patients with worse prognoses (positive nodes). Most regimens give these agents over 4-6 “courses.” Ongoing studies are examining the benefits of additions of even more types of chemotherapy agents, such as capecitabine (Xeloda™) and gemcitabine (Gemzar™), both of which have been shown to be very active in the metastatic setting.

In addition to new drugs, doctors have studied whether giving older drugs in new ways might be more beneficial than standard approaches. Unfortunately, a series of prospective randomized clinical trials demonstrated that higher doses than those used now were no more effective, and certainly contributed added toxicities. Interestingly, at least one large trial has shown that giving chemotherapy more frequently, or in a so-called “dose-dense” fashion every two weeks, is slightly but statistically more effective than giving it every three weeks. This approach requires use of expensive growth factor shots to keep a patient’s white blood cells in the safe range. However, dose dense chemotherapy is, surprisingly, less toxic in general and may cut several weeks off the time needed to deliver the same amount of treatment. An ongoing prospective randomized clinical trial is addressing whether even more frequent therapy (weekly) might be even more effective.

Anti-HER2 therapies

As noted, HER2 sits on the surface of a cancer cell and helps control the signals from outside the cell to the nucleus. The most important anti-HER2 therapy to date is called trastuzumab (Herceptin™). Trastuzumab is an antibody made originally by mice but which has now been “humanized” and is grown in large vats. It binds to HER2 and in ways that are not entirely clear, keeps it from working within the cell. Thus, trastuzumab does not work in cells that do not make HER2, as far as we can determine.

Trastuzumab has turned out to be a remarkable drug. It was first shown to be effective either by itself or with chemotherapy in patients with HER2 positive metastatic breast cancer. In fact, many doctors believe that there are selected patients in this situation who appear to be cured by trastuzumab, which as we have discussed is quite unusual. Nonetheless, most patients with metastatic breast cancer are not cured, even by trastuzumab. Trastuzumab has now been tested in five very large prospective randomized clinical trials in the adjuvant setting and found to reduce the risk of recurrence by 50% and the risk of dying by approximately one-third after only a few years of follow-up. Trastuzumab is now considered standard of care for most women with HER2 positive breast cancer.

In both the metastatic and adjuvant settings, trastuzumab is given intravenously every week or every 3 weeks. In the adjuvant setting, trastuzumab is given for approximately 12 months (although there are prospective randomized trials being conducted that address whether shorter or even longer therapy is preferable). Thus, addition of trastuzumab in the adjuvant setting is very inconvenient, since the chemotherapy regimens recommended for most women might only last 2-4 months. Thus, in the era prior to our use of trastuzumab, a patient would be completely finished with intravenous therapy. She might still need to take oral anti-estrogen therapy, but she would not have to make frequent visits to her doctor for prolonged infusions. Trastuzumab is also associated with a high financial cost. However, it is very well tolerated. A few patients have an allergic reaction to it the first time they get it, such as skin rash and breathing difficulties, much like some patients have allergies to penicillin and other drugs. However, unlike reactions to penicillin, allergic reactions to trastuzumab usually do not happen with later treatments. It does not cause nausea, vomiting, or hair loss. The main concern about trastuzumab relates to its effect on the heart. Trastuzumab causes a reduction in heart function in 3-5% of women who have previously had an anthracycline, although only approximately 1% of them have symptoms, and this syndrome is usually reversible by stopping the drug.

A new agent, called lapatinib (Tykerb®), is a small molecule that goes into the cell and blocks the transmission of the signal from HER2 to the nucleus. Lapatinib is quite active even in women for whom trastuzumab has quit working, it can be given orally, and it does not appear to increase the risk of heart failure in the same manner that trastuzumab does22. It does cause diarrhea and a skin rash.

New trials comparing trastuzumab by itself, lapatinib by itself, or a combination of the two are just starting for women with HER2 positive breast cancer.

Table 4.  Commonly Used Systemic Therapies for Breast Cancer

Class of Therapy	SubGroup	Specific Agents Available in US (Brand name)
Anti-estrogen (also called hormone therapy, or endocrine therapy)	SERMs	Tamoxifen (Nolvadex®) Toremifene (Fareston®) Raloxifene (Evista®)(prevention only)
	Inhibit ovarian function (premenopausal only)	Leuprolide (Lupron®) Goserelin (Zoladex®)
	Aromatase inhibitors (postmenopausal only)	Anastrozole (Arimidex®) Exemestane (Aromasin®) Letrozole (Femara®)
	Miscellaneous	Megestrol acetate (Megace®)
Chemotherapy	Alkylating Agents	Cyclophosphamide (Cytoxan®) Cisplatin (generic) Carboplatin (Paraplatin®)
	Anthracyclines	Doxorubicin (Adriamycin®) Doxorubicin liposomal (Doxil®) Epirubicin (Ellence®)
	Anti-metabolites	5-Fluoruracil (generic) Capecitabine (Xeloda®) Methotrexate (generic) Gemcitabine (Gemzar®)
	Anti-microtubules/Taxanes	Vinorelbine (Navelbine®) Paclitaxel (Taxol®) Docetaxel (Taxotere®) Paclitaxel-nanoparticle albumin (Abraxane®) Ixabepilone (Ixempra®)
Targeted Therapy	Anti-HER2	Trastuzumab (Herceptin®) Lapatinib (Tykerb®)
	Anti-angiogenic	Bevacizumab (Avastin®)

Notes :

1.   All of these agents are approved by the FDA for some indication, but not all are approved for breast cancer.

2.   This does not represent a complete list of all agents that have been reported to be active in breast cancer.

Anti-angiogenesis therapy

In 1971, the late Dr. Judah Folkman first proposed that cancers could only grow if they induced new blood vessel growth in surrounding normal tissues. This process is called neo-angiogenesis or neo-vascularization. Since that time, several laboratory-based studies have confirmed Dr. Folkman’s theory regarding the importance of neo-angiogenesis, and in the last few years several agents that are felt, at least in part, to prevent or even reverse this process have been shown to be effective in several types of cancers. In particular, a monoclonal antibody, bevacizumab (Avastin®) has been shown to double the number of women with metastatic breast cancer who respond to paclitaxel (Taxol®) chemotherapy and to delay the time until their disease progresses by about twice that of those treated with paclitaxel alone23. However, bevacizumab is associated with occasional major toxicities, and at least in the one large study that has been reported, overall survival was not improved. Therefore, at this writing, the FDA has not yet approved bevacizumab for breast cancer, although it has been approved for lung and colon cancers. Large trials investigating whether bevacizumab prevents recurrences and improves survival in the adjuvant setting are just getting underway.

Logistics of Primary and Adjuvant Therapy: Summing all of this section, the different types of treatments are usually given in the following sequence: surgery-chemotherapy-radiation-hormone therapy, with trastuzumab (Herceptin®) usually given at the same time or immediately after the chemotherapy and with the radiation and the hormone therapy. If a patient does not receive any one of these, she goes onto the next appropriate therapy. Surgical therapy and its recovery usually takes 3-4 weeks, chemotherapy usually takes 3-6 months, radiation usually takes 6-8 weeks, trastuzumab is usually given for 12 months, and hormone therapy is usually given for at least 5 years, and more recently for even longer.

Sometimes systemic therapy, especially chemotherapy, is given before the surgery. This strategy, called pre-operative, or neo-adjuvant, chemotherapy is usually given to patients with stage III breast cancer, and sometimes to patients with larger stage II lesions. Pre-operative chemotherapy does not improve survival compared to giving the same therapy after surgery, but it has been used to shrink cancers and permit breast conserving therapy in patients who would have otherwise needed a mastectomy. Pre-operative chemotherapy is also used in clinical studies to examine whether one or another type of therapy is working, since doctors can look at the remaining cancer tissue after the treatment at the time of surgery. Pre-operative anti-estrogen therapy has also been studied, particularly in older women with larger tumors, and found to be safe and effective. Ongoing prospective randomized trials are addressing the precise circumstances in which this approach might be useful.

Follow-up of Patients After Primary and Adjuvant Chemotherapy1

Once a patient has undergone her primary surgery and radiation and adjuvant chemotherapy, a major concern is to help her return to as normal a life as possible. Of course, for most women, breast cancer and its treatment induces profound life-changes, and few women ever return completely to the circumstances in which they lived before their diagnosis and treatment. Although most do resume remarkably normal lives, there are several special concerns and frequently asked questions.

1. What do I watch out for? After a diagnosis of breast cancer, many women find that the least symptom greatly raises anxiety levels that it might be an indication of recurrent cancer. It is important to remember that before you ever had breast cancer, you experienced minor symptoms, aches, and pains that were attributable to entirely benign sources, and you will get them still. Recurrent breast cancer is usually not subtle. If you have a new symptom that is not easily explained, lasts longer than usual for you, or is particularly severe or increasing in intensity, you should bring this to the attention of your physician. Likewise, if you notice a new lump or bump, in your breast or elsewhere, and it persists more than a few days or weeks, you should have it evaluated by whomever is serving as your main source of medical care (see below, #3, “Who should follow me and are there special medical concerns?”)

2. What tests should I get? It seems logical that doctors would screen patients who have previously had breast cancer with blood tests and radiographic studies (like bone, CT, MRI or PET scans) to find metastases before they cause symptoms. However, no study has ever shown that doing so results in a better way to treat patients, since these tests only detect a recurrence a few months, at most, before it was going to happen anyway. If we are going to treat a patient early, it should be done many years before the recurrence was going to happen. Indeed, that is what adjuvant systemic therapy is all about. Furthermore, these tests are fraught with false positive results (maybe as high as 50% of “positive” findings are NOT cancer), and therefore they will elevate anxiety levels (just the opposite of why most patients profess to want to have them performed) and may actually lead to harm if further diagnostic evaluations cause injury. Two large prospective randomized trials performed in the 1980s failed to demonstrate that patients screened for metastatic recurrences do better or feel better than unscreened ones.

However, it is important to screen for NEW primary cancers, in the breast or in other organs, using tests that are normally recommended for any woman. Therefore, a woman who has had breast cancer, just like any other woman, should have routine annual mammography (there is no reason to do it more often for most women), as well as routine Pap tests and colonoscopy (if she is over 50 and of average risk).

Lately, breast screening tests with higher sensitivity than mammography have been recommended, such as breast MRI or high resolution ultrasonography. We have discussed the pros and cons of doing these tests in addition to mammography above, and the same concerns pertain.

3. Who should follow me and are there special medical concerns? Who exactly follows a patient with breast cancer after treatment varies from practice to practice and there are no special guidelines. However, every woman should be certain that she is under the care of a primary practice family practitioner, internist, or gynecologist. There are a few special concerns regarding potential complications of treatment:

a. Heart disease. It is true that both radiation to the left breast (the side the heart is on) and the anthracycline chemotherapy agents (doxorubicin (Adriamycin®); epirubicin (Ellence®)) and trastuzumab (Herceptin®) can all cause heart damage. However, this is a relatively uncommon complication of radiation and the anthracyclines. Patients receiving trastuzumab are monitored with either echocardiograms or MUGA tests, both of which analyze cardiac function, approximately every three months during therapy. There is no particular routine screening or prophylactic therapy recommended for women who have received these treatments after they are finished. Symptoms such as being short of breath, having to sit up to sleep, leg swelling, and persistent cough should all be brought to the attention of your physician. It is important to be sure you don’t have high blood pressure, high cholesterol, or diabetes, and if you do that they are well-controlled. You should exercise and you should absolutely never smoke cigarettes. These recommendations are actually true whether you’ve had breast cancer or not!

b. Second Cancers. Patients who have had breast cancer are modestly at higher risk for a second breast cancer (and so should have routine annual mammography). Women with “genetic risk” (in other words, they are BRCA1 or 2 positive), are at higher risk for ovarian cancer, and may elect to have their ovaries removed. Radiation is associated with an elevated risk of some very rare cancers called sarcomas, but even when elevated, the absolute risk of these cancers is so low that nothing special is indicated to screen for them. The anthracyclines (doxorubicin (Adriamycin®) and epirubicin (Ellence®) are associated with an increased risk of leukemia (cancer of the white blood cells), but again this is still very uncommon and no special screening or prevention is necessary. Women who take tamoxifen have approximately double the risk of cancer of the endometrium (the lining of the uterus, or womb), but as with the cancers mentioned above, this is still very uncommon and no special screening or prevention is needed. However, if a woman on tamoxifen develops unusual pelvic discomfort or abnormal vaginal bleeding or spotting, she should bring this to the attention of her gynecologist immediately.

c. Psycho-Social/Cognitive Problems. Issues such as depression and failure to return to normal life are relatively common, and can be the result of many factors, including the diagnosis itself, its treatment, and other external causes. Of course, depression can occur as a disease itself. It is particularly important to know that episodes of depression may occur soon after finishing chemotherapy, at a time when most women hope they will get their lives back together. This syndrome may be very similar to post-partum depression. These symptoms need to be recognized and treated appropriately.

Many women complain of loss of memory and inability to think as well as they did before treatment. This syndrome has become known as cognitive dysfunction, or popularly, “chemo-brain.” There is not a great deal of rigorous research into the cause or treatment of this condition. In fact, it is not even clear that chemotherapy itself causes long-lasting cognitive dysfunction; rather, the turmoil caused by the diagnosis and treatment may result in anxiety, fear, confusion, and lack of an ability to concentrate. Regardless, at present there is no good screening test for it, and no way to prevent or treat this condition. Ongoing studies are addressing all of these issues.

d. Sexual Problems. Sexual problems after diagnosis and treatment of breast cancer are quite common. The diagnosis itself may cause psychological disturbance in libido (the desire to have sexual relations)., and of course treatment of the breast may create worrisome and on occasion profound cosmetic and therefore body-image problems. Chemotherapy may induce menopause in pre-menopausal women, and during chemotherapy many women lose libido. Anti-estrogen therapy is particularly bothersome for both pre- and post-menopausal patients, resulting in lower libido and physical problems, particularly vaginal dryness with pain on intercourse. Ideally, women with these symptoms would be treated with estrogen, which works quite well. However, a prospective randomized trial that compared replacement estrogen therapy plus tamoxifen to tamoxifen alone had to be stopped early due to increased recurrences in the women taking estrogen. Therefore, in women with ER positive breast cancer, estrogen replacement is strongly discouraged. It is not clear if estrogen use is safe or not in women with ER negative breast cancers.

Several studies have demonstrated that intra-vaginal estrogen creams or ointments effectively increase lubrication. However, the drug is readily absorbed from this area, and therefore may not be any safer than taking estrogen pills. Intra-vaginal preparations which release very low levels of estrogen over long periods of time have been reported to not result in higher levels of estrogen in the blood, but studies have shown that women who use these have secondary evidence of estrogen effect, such as lower cholesterol levels (we know that estrogen lowers cholesterol). Many, although not all, doctors discourage their use in ER positive women. There are several NON-hormonal vaginal lubricants on the market, such as Replens® and Astroglide®, which some women find helpful.

Treatment of Metastatic Breast Cancer²⁴

As noted, sadly, few if any patients who have documented metastatic disease (which is usually also causing symptoms) will be cured. However, the good news is that treatment for these women has substantially improved over the last 30 years to the extent that many can consider their condition to be chronic. In this case, most oncologists tell their patients that the goal of therapy is “palliation,” which means keeping her quality of life as high as possible for as long as possible. This goal can often be successfully achieved by picking the therapy most likely to work with the fewest side effects. In that regard, her doctor will likely recommend local therapies, such as surgery or radiation, for symptoms that are particularly acute and localized to one area (for example, pain in a bone), or systemic therapies when the symptoms are more widespread and the cancer is involving many organs.

As with adjuvant systemic therapies, metastatic treatments include anti-estrogen (also called hormone or endocrine therapies), chemotherapies, anti-HER2 therapies, and anti-angiogenic therapies. Whether to use these alone, or in combination, differs from patient to patient depending on her circumstance, but if used judiciously most patients can experience relief of their cancer-related symptoms without too many side effects from treatment.

Once a therapy is started, it should be stopped for one of two reasons: 1) it is causing so many side effects that even if it works, it is not worth it; or 2) it is not working. Doctors determine these two effects by following patients and taking a good history, performing a good physical examination, and monitoring certain blood tests and scans. All of these are synthesized to make a decision as to whether to continue that particular treatment or to go on to the next available one. If treated carefully, many patients may live productive and relatively symptom-free lives for long periods of time.

In addition to prospective randomized clinical trials (which are also called “Phase III” trials), studies to explore brand new drugs are also often offered to men with metastatic disease. These Phase I and Phase II trials are usually directed toward identifying the best dose and schedule of a drug or combination of drugs in regard to side effects, or they are designed to determine if the new strategy has sufficient activity to warrant a larger and more definitive, Phase III study. As discussed above, if you are in this situation, you might wish to explore participation in one of these studies with your caregiver.

SUPPORT GROUPS AND PSYCHO-SOCIAL HELP

The diagnosis of breast cancer is a life-changing event. Perhaps more than other cancers, breast cancer raises issues not only of a patient’s suffering and mortality due to the disease, but also a variety of body image, cosmetic, psychological, and social issues. Furthermore, as discussed, these problems may be induced by the treatment as often or more than by the disease itself. Few patients can handle a major, potentially life-threatening illness alone, and breast cancer is no exception. Women with this diagnosis are encouraged to be certain their family and loved ones are involved in decision-making and care. Furthermore, important physical and psychological symptoms should be brought the attention of your caregiver. In particular, symptoms of depression have been found to be much more common in women with breast cancer than in those who are otherwise of equal socio-economic status without the disease. These symptoms can be addressed at various levels: by your oncology team, by a trained social worker/psychologist, and often by the input of a psychiatry team. Anti-depressant therapy, used judiciously, can be quite helpful. However, as noted, it is important that the oncology and psychotherapy team be in contact, because some anti-depressant agents can interfere with tamoxifen’s activity.

Many cancer centers, clinics, and hospitals have established support groups for patients with similar circumstances and diseases. Breast cancer support groups have been well-established for years around the country, and many women find them very helpful in dealing with the complex issues surrounding diagnosis and treatment. Some patients find they only need and benefit from these groups for short periods of time, while others find them useful over years. Many years ago, an interesting prospective randomized trial suggested that women who underwent intensive psychosocial support, including support groups, had better survival than those who did not. However, a subsequent, larger study, failed to confirm this observation. Nonetheless, all studies have shown that women who are provided appropriate and adequate support have better quality of life as they face the challenges of treatment, and subsequent return to normal life, after a diagnosis of breast cancer.

Summary

Although breast cancer is common and still accounts for too much mortality and morbidity, a remarkable series of achievements has resulted in substantial improvement in survival. Treatments are not only more effective, they are, for the most part, easier to take than in the past, either because they are less toxic themselves or because treatments designed to avoid side effects, such as new anti-nausea medicines, are so effective.

Every woman should take steps to minimize the impact of breast cancer on her life:

1. Begin screening mammography at age 40

2. Report any suspicious breast lump or finding to your physician right away

3. If you are diagnosed with breast cancer, seek opinions regarding evaluation and care from qualified breast cancer experts

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